C-met modulator pharmaceutical compositions

ABSTRACT

Pharmaceutical compositions and unit dosage forms comprising Compound I are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a United States National Phase filing ofPCT/US2011/044378, filed Jul. 18, 2011, which claims priority to U.S.Provisional Application No. 61/365,253, filed Jul. 16, 2010, and U.S.Provisional Application No. 61/370,843, filed Aug. 5, 2010, the entirecontents of which is incorporated herein by reference.

FIELD OF THE INVENTION

Traditionally, dramatic improvements in the treatment of cancer areassociated with identification of therapeutic agents acting throughnovel mechanisms. One mechanism that can be exploited in cancertreatment is the modulation of protein kinase activity. Signaltransduction through protein kinase activation is responsible for manyof the characteristics of tumor cells. Protein kinase signaltransduction is particularly relevant in, for example, renal cancer,gastric cancer, head and neck cancers, lung cancer, breast cancer,prostate cancer, colorectal cancers, and hepatocellular carcinoma, aswell as in the growth and proliferation of brain tumor cells.

Protein kinases can be categorized as receptor type or non-receptortype. Receptor-type tyrosine kinases are comprised of a large number oftransmembrane receptors with diverse biological activity. For a detaileddiscussion of the receptor-type tyrosine kinases, see Plowman et al.,DN&P 7(6): 334-339, 1994. Since protein kinases and their ligands playcritical roles in various cellular activities, deregulation of proteinkinase enzymatic activity can lead to altered cellular properties, suchas uncontrolled cell growth that is associated with cancer. In additionto oncological indications, altered kinase signaling is implicated innumerous other pathological diseases, including, for example,immunological disorders, cardiovascular diseases, inflammatory diseases,and degenerative diseases. Protein kinases are therefore attractivetargets for small molecule drug discovery. Particularly attractivetargets for small-molecule modulation with respect to antiangiogenic andantiproliferative activity include receptor type tyrosine kinases c-Met,KDR, c-Kit, Axl, flt-3, and flt-4.

The kinase c-Met is the prototypic member of a subfamily ofheterodimeric receptor tyrosine kinases (RTKs), which include Met, Ron,and Sea. The endogenous ligand for c-Met is the hepatocyte growth factor(HGF), a potent inducer of angiogenesis. Binding of HGF to c-Met inducesactivation of the receptor via autophosphorylation resulting in anincrease of receptor dependent signaling, which promotes cell growth andinvasion. Anti-HOF antibodies or HGF antagonists have been shown toinhibit tumor metastasis in vivo (See Maulik et al Cytokine & GrowthFactor Reviews 2002 13, 41-59). c-Met overexpression has beendemonstrated on a wide variety of tumor types, including breast, colon,renal, lung, squamous cell myeloid leukemia, hemangiomas, melanomas,astrocytomas, and glioblastomas. Additionally, activating mutations inthe kinase domain of c-Met have been identified in hereditary andsporadic renal papilloma and squamous cell carcinoma. (See, e.g., Mauliket al., Cytokine & growth Factor reviews 2002 13, 41-59; Longati et al.,Curr Drug Targets 2001, 2, 41-55; Funakoshi et al., Clinica Chimica Acta2003 1-23).

Inhibition of epidermal growth factor (EGF), vascular endothelial growthfactor (VEGF), and ephrin signal transduction will prevent cellproliferation and angiogenesis, both of which are key cellular processesneeded for tumor growth and survival (Matter A., Drug Disc. Technol.20016, 1005-1024). Kinase KDR (refers to kinase insert domain receptortyrosine kinase) and flt-4 (fms-like tyrosine kinase-4) are both VEGFreceptors. EGF and VEGF receptors are desirable targets for smallmolecule inhibition. All members of the VEGF family stimulate cellularresponses by binding to tyrosine kinase receptors (the VEGFRs) on thecell surface, which causes them to dimerize and become activated throughtransphosphorylation. The VEGF receptors have an extracellular portionwith immunoglobulin-like domains, a single transmembrane spanningregion, and an intracellular portion containing a split tyrosine-kinasedomain. VEGF binds to VEGFR-1 and VEGFR-2. VEGFR-2 is known to mediatealmost all of the known cellular responses to VEGF.

Kinase c-Kit (also called stem cell factor receptor or steel factorreceptor) is a type 3 receptor tyrosine kinase (RTK) that belongs to theplatelet-derived growth factor receptor subfamily. Overexpression ofc-Kit and c-Kit ligand has been described in variety of human diseases,including human gastrointestinal stromal tumors, mastocytosis, germ celltumors, acute myeloid leukemia (AML), NK lymphoma, small-cell lungcancer, neuroblastomas, gynecological tumors, and colon carcinoma.Moreover, elevated expression of c-Kit may also relate to thedevelopment of neoplasia associated with neurofibromatosis type 1(NF-1), mesenchymal tumors GISTs, and mast cell disease, as well asother disorders associated with activated c-Kit.

Kinase Flt-3 (fms-like tyrosine kinase-3) is constitutively activatedvia mutation, either in the juxtamembrane region or in the activationloop of the kinase domain, in a large proportion of patients with AML(acute myeloid leukemia) (See Reilly, Leuk. Lymphoma, 2003, 44: 1-7).

Accordingly, small-molecule compounds that specifically inhibit,regulate, and/or modulate the signal transduction of kinases, includingc-Met, VEGFR2, KDR, c-Kit, Axl, flt-3, and flt-4, are particularlydesirable as a means to treat or prevent disease states that areassociated with abnormal cell proliferation and angiogenesis. One suchsmall-molecule is Compound I, know also by its chemical nameN-[4-[(6,7-Dimethoxy-4-quinoliny)oxy]phenyl]-N′-(4-fluorophenyl)-1,1-cyclopropanedicarboxamidewhich has the following chemical structure.

Compound I is disclosed and claimed in WO2005/030140, the entirecontents of which is herein incorporated by reference. WO2005/030140describes the synthesis of compound I (Table 2, Compound 12, Example 48)and discloses the therapeutic activity of this molecule to inhibit,regulate, and/or modulate the signal transduction of kinases (Assays,Table 4, entry 289). Compound I may be used as the malate salt.

Although therapeutic efficacy is the primary concern for a therapeuticagent, the pharmaceutical composition can be equally important to itsdevelopment. Generally, drug developers endeavor to discover apharmaceutical composition that possesses desirable properties, such assatisfactory water-solubility (including rate of dissolution), storagestability, hygroscopicity, and reproducibility, all of which can impactthe processability, manufacture, and/or bioavailability of the drug.Accordingly, discovery of pharmaceutical compositions that possess someor all of these desired properties is vital to drug development.

SUMMARY OF THE INVENTION

These and other needs are met by the present disclosure, which isdirected to a pharmaceutical composition comprising Compound I asprovided in Table 1.

TABLE 1 Ingredient (% w/w) Compound I 31.68 Microcrystalline Cellulose38.85 Lactose anhydrous 19.42 Hydroxypropyl Cellulose 3.00Croscarmellose Sodium 3.00 Total Intra-granular 95.95 Silicon dioxide,Colloidal 0.30 Croscarmellose Sodium 3.00 Magnesium Stearate 0.75 Total100.00

The disclosure is also directed to a pharmaceutical compositioncomprising Compound I as provided in Table 2.

TABLE 2 Ingredient (% w/w) Compound I 25.0-33.3 MicrocrystallineCellulose q.s Hydroxypropyl Cellulose 3   Poloxamer 0-3 CroscarmelloseSodium 6.0 Colloidal Silicon Dioxide 0.5 Magnesium Stearate 0.5-1.0Total 100   

The disclosure is further directed to a pharmaceutical compositioncomprising Compound I as provided in Table 3.

TABLE 3 Theoretical Quantity (mg/unit Ingredient dose) Compound I 100.0Microcrystalline Cellulose 155.4 PH-102 Lactose Anhydrous 60M 77.7Hydroxypropyl Cellulose, 12.0 EXF Croscarmellose Sodium 24 ColloidalSilicon Dioxide 1.2 Magnesium Stearate (Non- 3.0 Bovine) Opadry Yellow16.0 Total 416

In one aspect, Compound I is present in Tables 1, 2, and 3 as theL-malate salt.

The disclosure is also directed to a process of preparing apharmaceutical composition according to Tables 1, 2, or 3.

The disclosure is further directed to a method for treating cancer,comprising administering to a patient in need of such treatment apharmaceutical composition according to Tables 1, 2, or 3. Thedisclosure is also directed to a method for treating cancer, comprisingadministering to a patient in need of such treatment a pharmaceuticalcomposition according to Tables 1, 2, or 3 in combination with anothertherapeutic agent.

In these and other treatment aspects, the cancers to be treated includethe cancers disclosed in WO2005/030140, including pancreatic cancer,kidney cancer, liver cancer, prostate cancer, gastric cancer,gastroesophageal cancer, melanoma, lung cancer, breast cancer, thyroidcancer, and astrocytic tumors. More particularly, the cancers includepancreatic cancer, hepatocellular carcinoma (HCC), renal cell carcinoma,castration-resistant prostate cancer (CRPC), gastric or gastroesophagealjunction cancer, melanoma, small cell lung cancer (SCLC), ovariancancer, primary peritoneal or fallopian tube carcinoma, estrogenreceptor positive breast cancer, estrogen receptor/progesteronereceptor/HER2-negative (triple-negative) breast cancer, inflammatory(regardless of receptor status) breast cancer histology, non-small celllung cancer (NSCLC), and medullary thyroid cancer.

DETAILED DESCRIPTION

The disclosure is directed to a pharmaceutical formulation comprisingCompound I and pharmaceutically acceptable filler, binder, disintegrant,glidant, and lubricant, and optionally a film coating material, each ofwhich are described in greater detail in the following paragraphs.Examples of pharmaceutically acceptable fillers, binders, disintegrants,glidants, lubricants, and film coatings are set forth below and aredescribed in more detail in the Handbook of Pharmaceutical Excipients,Second Edition, Ed. A. Wade and P. J. Weller, 1994, The PharmaceuticalPress, London, England. The term excipient as used herein refers toinert materials which impart satisfactory processing and compressioncharacteristics into the formulation or impart desired physicalcharacteristics to the finished table.

Compound I Pharmaceutical Composition

The Compound I pharmaceutical composition is a tablet comprisingCompound I and excipients selected from the group consisting of afiller, a binder, a disintegrant, a glidant, and a lubricant, andoptionally may be coated or uncoated.

Compound I

In one embodiment, the pharmaceutical composition comprises Compound Ias the free base.

In another embodiment, the pharmaceutical composition comprises CompoundI as a hydrate.

In another embodiment, the pharmaceutical composition comprises CompoundI as a salt.

In another embodiment, the salt of Compound I is the malate salt.

In another embodiment, the malate salt is the L-malate salt of CompoundI, which has the following structure.

Compound I, L-Malate Salt

In a further embodiment, the malate salt is the D-malate salt. In afurther embodiment, the malate salt is the D,L-malate salt.

The malate salts of Compound I, particularly the L malate salt, have apreferred combination of pharmaceutical properties for development.Under the conditions of 25° C./60 percent relative humidity (RH) and 40°C./60 percent RH, the L-malate salt of Compound I showed no change inassay, purity, moisture, and dissolution. The DSC/TGA showed theL-malate salt of Compound I to be stable up to 185° C. No solvent losseswere observed. The uptake of water by the L-malate salt was reversiblewith a slight hysteresis. The amount of water taken up was calculated atabout 0.60 weight percent at 90 percent RH. The L-malate salt wassynthesized with good yield and purity greater than 90 percent and hadsufficient solubility for use in a pharmaceutical composition. Theamount of water associated with this salt was calculated at about 0.5weight percent by Karl Fischer analysis and correlates with TGA and GVSanalysis.

The L-malate salt of Compound I itself, and separately its crystallineand amorphous forms, exhibit beneficial properties over the free baseand the other salts of Compound I. For example, the hydrochloride saltof Compound I exhibits undesirable moisture sensitivity, changing phaseupon exposure to high humidity (75 percent RH) and high temperature (40°C.). The maleate salt had low solubility. The tartrate salt had lowcrystallinity and low solubility. The phosphate salt exhibited an 8percent weight gain due to absorption of H₂O, the highest among thesalts tested.

The water solubility of the various salts was determined using 10 mgsolids per mL water. The salts were prepared in a salt screen byreacting an acetone solution of the free base with stock tetrahydrofuran(THF) solutions of a range of acids in about a 1:1 molar ratio. Thetable below summarizes the water solubility and other data relating tothe free base and each salt.

Solubility (mg/ml) Free base <<0.001 very low solubility Propionate<<0.001 no salt formation; mixture of free base and acid Acetate <<0.001no salt formation; mixture of free base and acid Succinate 0.010 no saltformation; mixture of free base and acid Benzoate 0.005 no saltformation; mixture of free base and acid L-Lactate 0.015 Amorphous, saltPyrroglutamate 0.44 Amorphous, salt Glycolate 0.016 Amorphous, saltL-Ascorbate 0.053 low crystallinity Sulfate 0.004 Crystalline salt, lowsolubility Tosylate 0.007 Crystalline salt, low solubility Malonate0.003 Crystalline salt, low solubility 2,5dihydroxybenzoate <<0.001Crystalline Salt, low solubility Fumarate 0.008 Crystalline Salt, lowsolubility Citrate 0.002 Crystalline Salt, low solubility Mesylate 0.175Crystalline Salt; possible sulfonic acid formation when made withalcohol Esylate 0.194 Crystalline Salt; possible sulfonic acid formationwhen made with alcohol Benzenesulfonate 0.039 Crystalline Salt; possiblesulfonic acid formation when made with alcohol Chloride 0.070Crystalline but Hygroscopic; possible hydrate formation. Change in XRPDpattern upon exposure to humidity. Maleate 0.005 Crystalline salt,possible hydrate formation; low solubility; different XRPD patternobserved upon scale up (possible polymorphism issue) Phosphate 0.026Crystalline but Hygroscopic. L-Tartrate 0.014 Low degree ofcrystallinity; Hygroscopic. L-Malate 0.059 Crystalline; non-Hygroscopicwith no indication of hydrate formation. Suitable solubility, andchemical/physical stability.

In another embodiment, the L-malate salt of Compound I is amorphous orin substantially amorphous form. “Substantially amorphous” means thatmore than 50 percent of the Compound I L-malate salt is amorphous.

In another embodiment, the L-malate salt of Compound I is crystalline orin substantially crystalline form. “Substantially crystalline” meansthat more than 50 percent of the L-malate salt of Compound I iscrystalline. Two crystalline forms of the L-malate salt of Compound Iare the N-1 and/or the N-2 crystalline forms.

Similarly, in another embodiment, the D-malate salt of Compound I isamorphous or in substantially amorphous form. “Substantially amorphous”means that more than 50 percent of the D-malate salt of Compound I isamorphous.

In another embodiment, the D-malate salt of Compound I is crystalline orin substantially crystalline form. “Substantially crystalline” meansthat more than 50 percent of the D-malate salt of Compound I iscrystalline. Two crystalline forms of the D-malate salt of Compound Iare the N-1 and/or the N-2 crystalline form.

Similarly, in another embodiment, the D,L-malate salt of Compound I isamorphous or in substantially amorphous form. “Substantially amorphous”means that more than 50 percent of the D,L-malate salt of Compound I isamorphous.

In another embodiment, the D,L-malate salt of Compound I is crystallineor in substantially crystalline form. “Substantially crystalline” meansthat more than 50 percent of the D,L-malate salt of Compound I iscrystalline. Two crystalline forms of the D,L-malate salt of Compound Iare the N-1 and/or the N-2 crystalline form.

As is known in the art, the crystalline D malate salt will form the samecrystalline form and have the same properties as crystalline Compound I.See WO 2008/083319, which discusses the properties of crystallineenantiomers.

The crystalline N-1 form of the L-malate salt of Compound I and the N-1form of the D-malate salt of Compound I may be characterized by at leastone of the following:

-   -   (i) a solid state ¹³C NMR spectrum with peaks at 18.1, 42.9,        44.5, 70.4, 123.2, 156.2, 170.8, 175.7, and 182.1 ppm, ±0.2 ppm;    -   (ii) an x-ray powder diffraction pattern (CuKα λ=1.5418 Å)        comprising four or more peaks selected from: 6.4, 9.0, 12.0,        12.8, 13.5, 16.9, 19.4, 21.5, 22.8, 25.1, and 27.6°2θ±0.2° 2θ,        wherein measurement of the crystalline form is at an ambient        room temperature;    -   (iii) a solid state ¹⁵N NMR spectrum with peaks at 118.6, 119.6,        120.7, 134.8, 167.1, 176.0, and 180 ppm, ±0.2 ppm; and/or

Other solid state properties which may be used to characterize thecrystalline N-1 forms of the L-malate salt of Compound I and theD-malate salt of Compound I are discussed in WO 2010/083414, the entirecontents of which are incorporated herein by reference, and as describedin the Examples below. For crystalline Compound I L-malate salt, thesolid state phase and the degree of crystallinity remained unchangedafter exposure to 75 percent RH at 40° C. for 1 week.

The crystalline N-2 forms of the L- and D-malate salts of Compound I asdescribed here may be characterized by at least one of the following:

-   -   (i) a solid state ¹³C NMR spectrum with peaks at 23.0, 25.9,        38.0, 54.4, 56.11, 41.7, 69.7, 102.0, 122.5, 177.3, 179.3,        180.0, and 180.3, ±0.2 ppm;    -   (ii) an x-ray powder diffraction pattern (CuKα λ=1.5418 Å)        comprising four or more peaks selected from: 6.4, 9.1, 12.0,        12.8, 13.7, 17.1, 20.9, 21.9, 22.6, and 23.7° 2θ±0.2*2θ, wherein        measurement of the crystalline form is at an ambient room        temperature;    -   (iii) a solid state ¹⁵N NMR spectrum with peaks at 118.5, 120.8,        135.1, 167.3, and 180.1 ppm.

Other solid state properties may be used to characterize the crystallineN-2 forms of the L- and D-malate salts of Compound I are discussed in WO2010/083414.

In another embodiment, the crystalline form of the L-malate salt ofCompound I, as described herein in any of the aspects and/orembodiments, is substantially pure N-1 form.

In another embodiment, the disclosure relates to a crystalline form ofthe L-malate salt of Compound I in substantially pure N-2 form.

Another aspect of this disclosure relates to crystalline forms of theD,L-malate salt of Compound I. The D,L-malate salt is prepared fromracemic malic acid. The crystalline N-1 form of the D,L malate salt maybe characterized by at least one of the following:

-   -   (i) a solid state ¹³C NMR spectrum with four or more peaks        selected from 20.8, 26.2, 44.8, 55.7, 70.7, 100.4, 101.0, 114.7,        115.2, 116.0, 119.7, 120.4, 121.6, 124.4, 136.9, 138.9, 141.1,        145.7, 150.3, 156.5, 157.6, 159.6, 165.2, 167.4, 171.2, 176.3,        182.1 ppm, ±0.2 ppm;    -   (ii) a powder x-ray diffraction pattern (CuKα λ=1.5418 Å)        comprising four or more 2θ values selected from: 12.8, 13.5,        16.9, 19.4, 21.5, 22.8, 25.1, and 27.6, ±0.2°2θ, wherein        measurement of the crystalline form is at temperature of room        temperature; and/or    -   (iii) a solid state ¹⁵N NMR spectrum with peaks at 119.6, 134.7,        and 175.5 ppm, ±0.2 ppm.

Other solid state properties may be used to characterize the crystallineN-1 form of the D,L malate salt of Compound I, as discussed in WO2010/083414. In one embodiment, the N-1 Form of the D,L malate salt ofCompound I is characterized by unit cell parameters approximately equalto the following:

Cell dimensions: a=14.60 Å

-   -   b=5.20 Å    -   c=39.09 Å    -   α=90.0°    -   β=90.4°    -   γ=90.0°        Space group: P2₁/n        Molecules of Compound I/unit cell: 4        Volume=2969 Å³        Density (calculated)=1.422 g/cm³

The unit cell parameters of Form N-1 of the D,L malate salt of CompoundI were measured at a temperature of approximately 25° C., e.g., ambientor room temperature.

Each of the N-1 and N-2 crystalline forms of the L-malate salt and theD-malate salt of Compound I and the crystalline form N-1 of the D,Lmalate salt of Compound I have unique characteristics that candistinguish them one from another. These characteristics can beunderstood by comparing the physical properties of the solid stateforms. For example, Table 4 lists characteristic XRPD peak positions (°2θ±0.2° 2θ) for the crystalline D,L malate salt of Compound I, Form N-1and Forms N-1 and N-2 of the crystalline L-malate salt of Compound I.Amorphous forms do not display reflection peaks in their XRPD patterns.

TABLE 4 Characteristic diffraction peak positions (degrees 2θ ± 0.2) @RT, based on pattern collected with a diffractometer (CuKα) with aspinning capillary. Compound I Compound I Compound (III) L-Malate SaltL-Malate Salt D,L Malate Salt Form N-1 Form N-2 Form N-1 6.4 6.4 6.4 9.09.1 9.1 12.0 12.0 12.1 12.8 12.8 12.8 13.5 13.7 13.6 16.9 17.1 17.119.4* 20.9* 19.3 21.5* 21.9* 21.4 22.8* 22.6 22.8 25.1* 23.7 25.1 27.6*— 27.6 *unique reflections between Compound I L-Malate Salt, Form N-1and Compound I, L-Malate Salt, Form N-2.

The unique reflections between Forms N-1 and N-2 of the crystallineD-malate salt of Compound I are designated by an asterisk (*). Asdiscussed above, the D-malate salt of Compound I is an enantiomer of theL-malate salt of Compound I and thus, Form N-1 of the D-malate salt ofCompound I will have the same characteristic reflection pattern andunique peaks as those listed in Table 4 for the L-malate salt ofCompound I, Form N-1. Likewise, Form N-2 of the D-malate salt ofCompound I will have the same characteristic reflection pattern andunique peaks as those listed in Table 2 for the L-malate salt ofCompound I, Form N-2. The L- and D-malate salts of Compound I aredistinct from one another based on their absolute stereochemistry, i.e.,the L-malate salt versus the D-malate salt, respectively. Thecrystalline D,L malate salt of Compound I, Form N-1, is distinct as theD,L-malate salt.

The characteristic peaks from the solid state NMR may also serve todistinguish the crystalline and amorphous forms disclosed herein. Forexample, Table 5 lists characteristic solid state ¹³C NMR peaks for thecrystalline D,L-malate salt of Compound I, Form N-1, crystallineL-malate salt of Compound I, Forms N-1 and N-2, and the amorphous formof Compound I.

TABLE 5 Solid State Carbon-13 NMR Resonances (ppm, ±0.2 ppm) (I), (III),Form (I), (I) Form N-1 Form N-2 N-1 Amorphous 18.1 23.0 20.8 27.2 42.925.9 26.2 33.8 44.5 38.0 44.8 142.9 54.4 54.4 70.7 — 56.1 56.1 114.7 —70.4 41.7 141.1 — 123.2  69.7 145.7 — 156.2  102.0 176.3 — 170.8  122.5182.1 — 175.7  177.3 — — 182.1  179.3 — — — 180.0 — — — 180.3 — —

The solid state ¹⁹F and ¹⁵N NMR spectra, discussed below, provide datafor similar comparison and characterization. As discussed above, beingan enantiomer of the L-malate salt of Compound I, crystalline Forms N-1and N-2 and the amorphous form of the D-malate salt of Compound I havethe same solid state NMR resonances, and unique peaks between them, asthose provided for Forms N-1 and N-2 of crystalline L-malate salt ofCompound I.

The crystalline form of the L-malate salt and/or the D-malate salt ofCompound I can occur as mixtures. The mixtures may have from greaterthan zero weight percent to less than 100 weight percent of the L-malatesalt form and from less than 100 weight percent to greater than zeroweight percent D-malate salt form, based on the total weight of L-malatesalt form and D-malate salt form. In another embodiment, the mixturecomprises from about 1 to about 99 weight percent of the L-malate saltform and from about 99 to about 1 weight percent of the D-malate saltform, based on the total weight of the L-malate salt form and theD-malate salt form in said mixture. In a further embodiment, the mixturecomprises from about 90 weight percent to less than 100 weight percentL-malate salt form and from greater than zero weight percent to about 10weight percent D-malate salt form, based on the total weight of theL-malate salt form and the D-malate salt form. Accordingly, the mixturemay have 1 to 10 percent by weight of the L-malate salt form; 11 to 20percent by weight of the L-malate salt form; 21 to 30 percent by weightof the L-malate salt form; 31 to 40 percent by weight of the L-malatesalt form; 41 to 50 percent by weight of the L-malate salt form; 51 to60 percent by weight of the L-malate salt form; 61 to 70 percent byweight of the L-malate salt form; 71 to 80 percent by weight of theL-malate salt form; 81 to 90 percent by weight of the L-malate saltform; or 91 to 99 percent by weight of the L-malate salt form with theremaining weight percentage of malate salt being that of the D-malatesalt form.

Filler

As indicated above, the pharmaceutical composition containing Compound Icomprises a filler. Fillers are inert ingredients added to adjust thebulk in order to produce a size practical for compression. Examples offillers include sodium starch glycolate, corn starch, talc, sucrose,dextrose, glucose, lactose, xylitol, fructose, sorbitol, calciumphosphate, calcium sulfate, calcium carbonate, and the like, or mixturesthereof. Microcrystalline cellulose may also be used as a filler and maybe any suitable form of microcrystalline cellulose as is known and usedin the tabletting art. Preferably, a mixture of lactose andmicrocrystalline cellulose is used as the filler. In one embodiment, thelactose is anhydrous lactose sold as Lactose 60M, which is readilycommercially available from a number of suppliers. In one embodiment,the microcrystalline cellulose is Avicel PH-102, which is alsocommercially available.

Preferably, filler(s) are present in an amount of from about 50 to about70 percent, and more preferably from about 57 to about 67 percent, byweight on a solids basis of the directly compressible formulation.Preferably, lactose is present in an amount of from about 18 to 22percent by weight. Preferably, the microcrystalline cellulose is presentin an amount of from about 38 to 40 percent by weight.

Binder

The pharmaceutical composition containing Compound I also comprises abinder. Binders are added to powders to impart cohesive qualities to thepowder, which allows the compressed tablet to retain its integrity. Thebinder can be any pharmaceutically acceptable binder available in thetabletting art, such as acacia, alginic acid, carbomer,carboxymethylcellulose sodium, dextrin, ethylcellulose, gelatin, guargum, hydrogenated vegetable oil (type I), hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose,magnesium aluminum silicate, maltodextrin, methylcellulose,polymethacrylates, povidone, pregelatinized starch, sodium alginate,starch, zein, and the like, or mixtures thereof.

The preferred binder is hydroxypropyl cellulose preferably in an amountof from about 2 to about 4 percent by weight on a solid basis of thedirectly compressible formulation. In one embodiment, the hydroxypropylcellulose is commercially available Klucel EXF.

Disintegrant

The pharmaceutical composition containing Compound I also comprises adisintegrant. A disintegrant is a substance or a mixture of substancesadded to facilitate breakup or disintegrate after administration. Thedisintegrant may be any pharmaceutically acceptable disintegrantavailable in the tabletting art, including alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidalsilicon dioxide, croscarmellose sodium, crospovidone, guar gum,magnesium aluminum silicate, methylcellulose, microcrystallinecellulose, polyacrilin potassium, powdered cellulose, pregelatinizedstarch, sodium alginate, starch, and the like, or mixtures thereof.

The preferred disintegrant is croscarmellose sodium, in an amount offrom about 4 to about 8 percent by weight, on a solid basis of thedirectly compressible formulation. In one embodiment, the croscarmellosesodium is commercially available Ac-Di-Sol.

Glidant

The pharmaceutical composition containing Compound I also comprises aglidant. The glidant may be any pharmaceutically acceptable glidantwhich contributes to the compressibility, flowability, and homogeneityof the formulation and which minimizes segregation and does notsignificantly interfere with the release mechanism of the binders as setforth above. Preferably, the glidant is selected to improve the flow ofthe formulation. Silicon dioxide, particularly colloidal silicondioxide, is preferred as a glidant.

The glidant is used in an amount of from about 0.2 to about 0.6 percentby weight on a solid basis of the directly compressible formulation.

Lubricant

The pharmaceutical composition containing Compound I also comprises alubricant. Lubricants are employed to prevent adhesion of the tabletmaterial to the surface of dyes and punches. The lubricant may be anypharmaceutically acceptable lubricant which substantially preventssegregation of the powder by contributing to homogeneity of theformulation and which exhibits good flowability. Preferably, thelubricant functions to facilitate compression of the tablets andejection of the tablets from the die cavity. Such lubricants may behydrophilic or hydrophobic, and examples include magnesium stearate,Lubritab™, stearic acid, talc, and other lubricants known in the art orto be developed which exhibit acceptable or comparable properties, ormixtures thereof. Examples of lubricants include calcium stearate,glyceryl monostearate, glyceryl palmitostearate, hydrogenated castoroil, hydrogenated vegetable oil, light mineral oil, magnesium stearate,mineral oil, polyethylene glycol, sodium benzoate, sodium laurylsulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, andthe like, or mixtures thereof.

The lubricant should be selected to aid in the flow of the powder in thehopper and into the die. Magnesium stearate exhibits excellentproperties in combination with the other preferred excipients of theformulation. Magnesium stearate contributes to reducing friction betweenthe die wall and tablet formulation during compression, as well as tothe easy ejection of the Compound I tablets. It also resists adhesion topunches and dies.

Preferably, the lubricant is magnesium stearate (non-bovine) used in anamount of from about 0.5 to about 1.0 percent by weight on a solid basisof the directly compressible formulation.

Film Coating

The pharmaceutical composition containing Compound I also comprises anoptional film coating. The film coat concentration can be about 1 toabout 10 percent by weight on a solid basis of the directly compressibleformulation. Film coating suspensions may include combinations of thefollowing components: hypromeollose, carboxymethylcellulose sodium,carnauba wax, cellulose acetate phthalate, cetyl alcohol, confectioner'ssugar, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, liquid glucose, maltodextrin,methyl cellulose, microcrystalline wax, Opadry and Opadry II,polymethacrylates, polyvinyl alcohol, shellac, sucrose, talc, titaniumdioxide, and zein.

Preferably the film coating comprises commercially available OpadryYellow.

In one embodiment, the tablet composition comprises

30-32 percent by weight of Compound I in at least one of the formsdisclosed herein;

50-70 percent by weight of a filler;

2-4 percent by weight of a binder;

4-8 percent by weight a disintegrant; and

0.2-0.6 percent by weight of a glidant; and 0.5-1 percent by weight of alubricant.

In another embodiment, the tablet composition comprises:

30-32 percent by weight of Compound I in at least one of the formsdisclosed herein;

50-70 percent by weight of a filler;

2-4 percent by weight of a binder;

4-8 percent by weight a disintegrant; and

0.2-0.6 percent by weigh of a glidant; and 0.5-1 percent by weight of alubricant;

-   -   wherein the composition is coated.

In another embodiment, the tablet composition comprises:

Weight/Weight Component Percent Compound I 25-29 MicrocrystallineCellulose q.s. Lactose Anhydrous 40-44 Hydroxypropyl Cellulose 2-4Croscarmellose Sodium 2-8 Colloidal Silicon Dioxide 0.1-0.4 MagnesiumStearate 0.7-0.9 Total 100

In another embodiment, the tablet compositions of this disclosurecontain from 10 to about 200 mg of Compound I in at least one of theforms described herein. In another embodiment, the tablet compositionsof this disclosure contain from 20 to 100 mg of Compound I. In anotherembodiment, the tablet compositions contain 20, 25, 50, 60, 75, 80, or100 mg of Compound I.

In other embodiments, the tablet compositions are summarized in Tables1, 2, and 3. The compound I used in these and other compositionsdisclosed herein is the L-malate salt Compound I. In the tables, theweight of Compound I refers to the amount ofN-[4-[(6,7-Dimethoxy-4-quinolinyl)oxy]phenyl]-N′-(4-fluorophenyl)-1,1-cyclopropanedicarboxamidein the tablet. The skilled artisan will recognize that a certain amountof the Compound I L-malate salt is required to provide the weightslisted in the tables. Thus, for example, in Table 3, 126.7 mg ofCompound I L-malate salt is required to provide 100 mg of Compound I.Proportionally smaller or larger amounts of Compound I L-malate salt arerequired for tablet compositions containing less or more of Compound I.

Process

In another aspect, the disclosure is directed to a process for makingpharmaceutical formulations comprising Compound I. In one embodiment,the formulation is a tablet formulation.

In another embodiment, the process comprises mixing Compound I with oneor more of the pharmaceutical excipients. The mixture is then taken upin an aqueous solution containing a binder to form a binder solution.The binder solution is granulated using a granulation technique known inthe art. For example, the granulation method may comprise wet high sheargranulation using a wet high shear granulator. The resulting wetgranules are then screened and dried using fluid bed drying or the like.The dried granules are then milled. The resulting dry milled granulesare then mixed with a glidant and a disintegrant to form anextra-granular blend. A lubricant is then blended into the extraganularblend to form the final blend. The final blend is subsequentlycompressed to form the compressed tablet, which may be film coated.

More particularly, the process comprises delumping Compound I as neededprior to mixing with the excipients. Delumping ensures that the CompoundI mixes homogeneously with the other excipients during the formulationprocess. Delumped Compound I is then mixed with microcrystallinecellulose, such as Avicel PH102, lactose (anhydrous, 60M), andcroscarmellose sodium. This mixture is then combined with EXF gradehydroxypropoyl cellulose in water to form a binder solution, which isthen wet high shear granulated. The resulting wet granules are wetscreened and then fluid bed dried according to methods available to theskilled artisan. The resulting dried granules are milled and combinedwith colloidal silicon dioxide and croscarmellose sodium. Magnesiumstearate is added to the mixture. This final blend is then ready fortablet compression. The resulting uncoated core tablets are subsequentlyfilm coated. The film coating comprises Opadry Yellow, which containshypromellose, titanium dioxide, triacetin, and iron oxide yellow.

More particularly, the formulation process comprises:

-   -   a) Delumping unmilled Compound I;    -   b) Premixing the delumped Compound I with Avicel PH102, lactose        anhydrous 60M, and croscarmellose sodium to form a binder        solution;    -   c) Wet high shear granulation of the binder solution to produce        wet granules;    -   d) Wet screening of the wet granules to produce wet screened        granules;    -   e) Fluid bed drying of the wet screened granules to produce        dried granules;    -   f) Dry milling of the dried granules to produce dried milled        granules;    -   g) Blending the dried milled granules with colloidal silicon and        croscarmellose to produce an extragranular blend;    -   h) Lubricant blending of the extragranular blend and magnesium        stearate to produce a final blend;    -   i) Tablet compression of the final blend to form an uncoated        core tablet; and    -   j) Film coating of the uncoated core tablet.        Methods of Treatment

Another aspect of this disclosure relates to a method of treatingcancer, using a pharmaceutical composition containing Compound I in atleast one of its forms, either alone or in combination with anothertherapeutic agent. The cancer being treated is selected from stomachcancer, esophageal carcinoma, kidney cancer, liver cancer, ovariancarcinoma, cervical carcinoma, large bowel cancer, small bowel cancer,brain cancer (including astrocytic tumor, which includes glioblastoma,giant cell glioblastoma, gliosarcoma, and glioblastoma witholigodendroglial components), lung cancer (including non-small cell lungcancer), bone cancer, prostate carcinoma, pancreatic carcinoma, skincancer, bone cancer, lymphoma, solid tumors, Hodgkin's disease,non-Hodgkin's lymphoma, or thyroid cancer (including medullary thyroidcancer). More particularly, the cancer is pancreatic cancer,hepatocellular carcinoma (HCC), renal cell carcinoma,castration-resistant prostate cancer (CRPC), gastric or gastroesophagealjunction cancer, melanoma, small cell lung cancer (SCLC), ovariancancer, primary peritoneal or fallopian tube carcinoma, estrogenreceptor positive breast cancer, estrogen receptor/progesteronereceptor/HER2-negative (triple-negative) breast cancer, inflammatory(regardless of receptor status) breast cancer, non-small cell lungcancer (NSCLC), or medullary thyroid cancer.

Tyrosine kinase inhibitors have also been used to treat non-small celllung cancer (NSCLC). Gefitinib and erlotinib are angiogenesis inhibitorsthat target receptors of an epidermal growth factor called tyrosinekinase. Erlotinib and Gefitinib are currently being used for treatingNSCLC. Another aspect of this disclosure relates to a method of treatingnon-small cell lung cancer (NSCLC) comprising administering to thesubject in need of the treatment a therapeutically effective amount ofCompound I in at least one of the forms described herein,pharmaceutically formulated as described herein, optionally incombination with Erlotinib or Gefitinib. In another embodiment, thecombination is with Erlotinib.

In another embodiment, the cancer is non-small cell lung cancer (NSCLC),and the method comprises administering to the subject in need of thetreatment a therapeutically effective amount of Erlotinib or Gefitinibin combination with at least one of the forms of Compound I in at leastone of the forms described herein, pharmaceutically formulated asdescribed herein. The method of treatment may be practiced byadministering a tablet formulation of at Compound I in at least one ofthe forms described herein, pharmaceutically formulated as describedherein.

Another aspect of this disclosure relates to a method of treating anastrocytic tumor (which includes glioblastoma, giant cell glioblastoma,gliosarcoma, and glioblastoma with oligodendroglial components)comprising administering to the subject in need of the treatment atherapeutically effective amount of Compound I in at least one of theforms described herein, pharmaceutically formulated as described herein.

Another aspect of this disclosure relates to a method of treatingthyroid cancer (including medullary thyroid cancer) comprisingadministering to the subject in need of the treatment a therapeuticallyeffective amount of Compound I in at least one of the forms describedherein, pharmaceutically formulated as described herein.

Another aspect of this disclosure relates to a method of treatinghepatocellular carcinoma comprising administering to the subject in needof the treatment a therapeutically effective amount of Compound I in atleast one of the forms described herein, pharmaceutically formulated asdescribed herein.

Another aspect of this disclosure relates to a method of treating renalcell carcinoma comprising administering to the subject in need of thetreatment a therapeutically effective amount of Compound I in at leastone of the forms described herein, pharmaceutically formulated asdescribed herein.

Another aspect of this disclosure relates to a method of treatingcastration resistant prostate cancer comprising administering to thesubject in need of the treatment a therapeutically effective amount ofCompound I in at least one of the forms described herein,pharmaceutically formulated as described herein. The amount administeredcan be a therapeutically effective amount.

Another aspect of this disclosure relates to a method of breast cancercomprising administering to the subject in need of the treatment atherapeutically effective amount of Compound I in at least one of theforms described herein, pharmaceutically formulated as described herein.

Another aspect of this disclosure relates to a method of treatingovarian cancer comprising administering to the subject in need of thetreatment a therapeutically effective amount of Compound I in at leastone of the forms described herein, pharmaceutically formulated asdescribed herein.

Another aspect of this disclosure relates to a method of treatingdiseases or disorders associated with uncontrolled, abnormal, and/orunwanted cellular activities. The method comprises administering to thesubject in need of the treatment a therapeutically effective amount ofCompound I in at least one of the forms described herein,pharmaceutically formulated as described herein.

A “therapeutically effective amount of the active compounds”, or acrystalline or amorphous form of the active compound(s) to inhibit,regulate, and/or modulate the signal transduction of kinases (discussedhere concerning the pharmaceutical compositions) refers to an amountsufficient to treat a patient suffering from any of a variety of cancersassociated with abnormal cell proliferation and angiogenesis. Atherapeutically effective amount according to this disclosure is anamount therapeutically useful for the treatment or prevention of thedisease states and disorders discussed herein. Compound I possesstherapeutic activity to inhibit, regulate, and/or modulate the signaltransduction of kinases such as described in WO 2005/030140.

The actual amount required for treatment of any particular patient willdepend upon a variety of factors, including the disease state beingtreated and its severity; the specific pharmaceutical compositionemployed; the age, body weight, general health, sex, and diet of thepatient; the mode of administration; the time of administration; theroute of administration; the rate of excretion of the activecompound(s), or a crystalline form of the active compound(s), accordingto this disclosure; the duration of the treatment; any drugs used incombination or coincidental with the specific compound employed; andother such factors well known in the medical arts. These factors arediscussed in Goodman and Gilman's “The Pharmacological Basis ofTherapeutics,” Tenth Edition, A. Gilman, J. Hardman and L. Limbird,eds., McGraw-Hill Press, 155-173, 2001, which is incorporated herein byreference. The active compound(s), or a crystalline form of activecompound(s), according to this disclosure, and pharmaceuticalcompositions comprising them, may be used in combination with anticanceror other agents that are generally administered to a patient beingtreated for cancer. They may also be co-formulated with one or more ofsuch agents in a single pharmaceutical composition.

EXAMPLES

The disclosure is illustrated further by the following examples inScheme 1 and the description thereof, which are not to be construed aslimiting the invention in scope or spirit to the specific proceduresdescribed in them. Those having skill in the art will recognize that thestarting materials may be varied and additional steps employed toproduce compounds encompassed by the invention, as demonstrated by thefollowing examples. Those skilled in the art will also recognize that itmay be necessary to utilize different solvents or reagents to achievesome of the above transformations.

Unless otherwise specified, all reagents and solvents are of standardcommercial grade and are used without further purification. Theappropriate atmosphere to run the reaction under, for example, air,nitrogen, hydrogen, argon and the like, will be apparent to thoseskilled in the art.

Example 1 Preparation of Compound I and Compound I and the L-Malate Saltof Compound I

A synthetic route that can be used for the preparation ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideand the L-malate salt thereof is depicted in Scheme 1.

Preparation of 4-Chloro-6,7-dimethoxy-quinoline

A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol(47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heatedto approximately 60° C., and phosphorus oxychloride (POCl₃, 130.6 kg)was added. After the addition of POCl₃, the temperature of the reactionmixture was raised to approximately 77° C. The reaction was deemedcomplete (approximately 13 hours) when less than 3% of the startingmaterial remained (in-process high-performance liquid chromatography[HPLC] analysis). The reaction mixture was cooled to approximately 2-7°C. and then quenched into a chilled solution of dichloromethane (DCM,482.8 kg), 26% NH₄OH (251.3 kg), and water (900 L). The resultingmixture was warmed to approximately 20-25° C., and phases wereseparated. The organic phase was filtered through a bed of AW hyflosuper-cel NF (Celite™; 5.4 kg), and the filter bed was washed with DCM(118.9 kg). The combined organic phase was washed with brine (282.9 kg)and mixed with water (120 L). The phases were separated, and the organicphase was concentrated by vacuum distillation with the removal ofsolvent (approximately 95 L residual volume). DCM (686.5 kg) was chargedto the reactor containing organic phase and concentrated by vacuumdistillation with the removal of solvent (approximately 90 L residualvolume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged, and thetemperature of the mixture was adjusted to −20 to −25° C. and held for2.5 hours, resulting in solid precipitate which was then filtered andwashed with n-heptane (92.0 kg) and dried on a filter at approximately25° C. under nitrogen to afford the title compound. (35.6 kg).

Preparation of 4-(6,7-Dimethoxy-quinoline-4-yloxy)-phenylamine

4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline(35.3 kg), sodium t-butoxide (21.4 kg), and DMA (167.2 kg) at 20-25° C.This mixture was then heated to 100-105° C. for approximately 13 hours.After the reaction was deemed complete as determined using in-processHPLC analysis (less than 2% starting material remaining), the reactorcontents were cooled at 15-20° C., and water (pre-cooled, 2 to 7° C.,587 L) was charged at a rate to maintain 15-30° C. temperature. Theresulting solid precipitate was filtered and washed with a mixture ofwater (47 L) and DMA (89.1 kg) and again with water (214 L). The filtercake was then dried at approximately 25° C. on filter to yield crude4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (59.4 kg wet, 41.6 kgdry calculated based on LOD). Crude4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed(approximately 75° C.) in a mixture of tetrahydrofuran (THF, 211.4 kg)and DMA (108.8 kg) for approximately 1 hour, then cooled to 0-5° C., andaged for approximately 1 hour, after which time the solid was filtered,washed with THF (147.6 kg), and dried on a filter under vacuum atapproximately 25° C. to yield4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (34.0 kg).

Alternative Preparation of4-(6,7-Dimethoxy-quinoline-4-yloxy)-phenylamine

4-chloro-6,7-dimethoxyquinoline (34.8 kg), 4-Aminophenol (30.8 kg), andsodium tert pentoxide (1.8 equivalents) 88.7 kg, 35 wt percent in THF)were charged to a reactor, followed by N,N-dimethylacetamide (DMA, 293.3kg). This mixture was then heated to 105-115° C. for approximately 9hours. After the reaction was deemed complete as determined usingin-process HPLC analysis (less than 2 percent starting materialremaining), the reactor contents were cooled at 15-25° C., and water(315 kg) was added over a two hour period while maintaining thetemperature between 20 and 30° C. The reaction mixture was then agitatedfor an additional hour at 20 to 25° C. The crude product was collectedby filtration and washed with a mixture of water (88 kg) and DMA (82.1kg), followed by water (175 kg). The product was dried on a filter drierfor 53 hours. The LOD showed less than 1% weight/weight (w/w).

In an alternative procedure, 1.6 equivalents of sodium tert-pentoxidewere used, and the reaction temperature was increased from 110-120° C.In addition, the cool down temperature was increased to 35-40° C., andthe starting temperature of the water addition was adjusted to 35-40°C., with an allowed exotherm to 45° C.

Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid

Triethylamine (19.5 kg) was added to a cooled (approximately 5° C.)solution of cyclopropane-1,1-dicarboxylic acid (24.7 kg) in THF (89.6kg) at a rate such that the batch temperature did not exceed 5° C. Thesolution was stirred for approximately 1.3 hours, and then thionylchloride (23.1 kg) was added, keeping the batch temperature below 10° C.When the addition was complete, the solution was stirred forapproximately 4 hours, keeping the temperature below 10° C. A solutionof 4-fluoroaniline (18.0 kg) in THF (33.1 kg) was then added at a ratesuch that the batch temperature did not exceed 10° C. The mixture wasstirred for approximately 10 hours, after which the reaction was deemedcomplete. The reaction mixture was then diluted with isopropyl acetate(218.1 kg). This solution was washed sequentially with aqueous sodiumhydroxide (10.4 kg, 50 percent dissolved in 119 L of water) furtherdiluted with water (415 L), then with water (100 L), and finally withaqueous sodium chloride (20.0 kg dissolved in 100 L of water). Theorganic solution was concentrated by vacuum distillation (100 L residualvolume) below 40° C., followed by the addition of n-heptane (171.4 kg),which resulted in the precipitation of solid. The solid was recovered byfiltration and washed with n-Heptane (102.4 kg), resulting in wet crude,1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (29.0 kg). Thecrude, 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid wasdissolved in methanol (139.7 kg) at approximately 25° C. followed by theaddition of water (320 L), resulting in slurry which was recovered byfiltration, washed sequentially with water (20 L) and n-heptane (103.1kg), and then dried on the filter at approximately 25° C. under nitrogento afford the title compound (25.4 kg).

Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonylchloride

Oxalyl chloride (12.6 kg) was added to a solution of1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (22.8 kg) in amixture of THF (96.1 kg) and N,N-dimethylformamide (DMF; 0.23 kg) at arate such that the batch temperature did not exceed 25° C. This solutionwas used in the next step without further processing.

Alternative Preparation of1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride

A reactor was charged with1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (35 kg), DMF(344 g), and THF (175 kg). The reaction mixture was adjusted to 12-17°C., and then to the reaction mixture was charged with oxalyl chloride(19.9 kg) over a period of 1 hour. The reaction mixture was leftstirring at 12-17° C. for 3 to 8 hours. This solution was used in thenext step without further processing.

Preparation of cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide

The solution from the previous step containing1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride was added toa mixture of compound 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine(23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7 kg) and water(116 L) at a rate such that the batch temperature did not exceed 30° C.When the reaction was complete (in approximately 20 minutes), water (653L) was added. The mixture was stirred at 20-25° C. for approximately 10hours, which resulted in the precipitation of the product. The productwas recovered by filtration, washed with a pre-made solution of THF(68.6 kg) and water (256 L), and dried first on a filter under nitrogenat approximately 25° C. and then at approximately 45° C. under vacuum toafford the title compound (41.0 kg, 38.1 kg, calculated based on LOD).

Alternative Preparation of cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide

A reactor was charged with4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (35.7 kg, 1 equivalent),followed by 412.9 kg THF. To the reaction mixture was charged a solutionof 48.3 K₂CO₃ in 169 kg water. The acid chloride solution described inthe Alternative Preparation of1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride above wastransferred to the reactor containing4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine while maintaining thetemperature between 20-30° C. over a minimum of two hours. The reactionmixture ws stirred at 20-25° C. for a minimum of three hours. Thereaction temperature was then adjusted to 30-25° C., and the mixture wasagitated. The agitation was stopped, and the phases of the mixture wereallowed to separate. The lower aqueous phase was removed and discarded.To the remaining upper organic phase was added water (804 kg). Thereaction was left stirring at 15-25° C. for a minimum of 16 hours.

The product precipitated. The product was filtered and washed with amixture of water (179 kg) and THF (157.9 kg) in two portions. The crudeproduct was dried under a vacuum for at least two hours. The driedproduct was then taken up in THF (285.1 kg). The resulting suspensionwas transferred to reaction vessel and agitated until the suspensionbecame a clear (dissolved) solution, which required heating to 30-35° C.for approximately 30 minutes. Water (456 kg) was then added to thesolution, as well as SDAG-1 ethanol (20 kg) (ethanol denatured withmethanol over two hours). The mixture was agitated at 15-25° C. for atleast 16 hours. The product was filtered and washed with a mixture of143 kg water (143 kg) and THF (126.7 kg) in two portions. The productwas dried at a maximum temperature set point of 40° C.

In an alternative procedure, the reaction temperature during acidchloride formation was adjusted to 10-15° C. The recrystallizationtemperature was changed from 15-25° C. to 45-50° C. for 1 hour and thencooled to 15-25° C. over 2 hours.

Preparation of cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide, (L) malate salt

Cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (1-5; 13.3 kg), L-malic acid (4.96 kg), methylethyl ketone (MEK; 188.6 kg), and water (37.3 kg) were charged to areactor, and the mixture was heated to reflux (approximately 74° C.) forapproximately 2 hours. The reactor temperature was reduced to 50 to 55°C., and the reactor contents were filtered. These sequential stepsdescribed above were repeated two more times starting with similaramounts of 1-5 (13.3 kg), L-Malic acid (4.96 kg), MEK (198.6 kg), andwater (37.2 kg). The combined filtrate was azeotropically dried atatmospheric pressure using MEK (1133.2 kg) (approximate residual volume711 L; KF≦0.5% w/w) at approximately 74° C. The temperature of thereactor contents was reduced to 20 to 25° C. and held for approximately4 hours, resulting in solid precipitate which was filtered, washed withMEK (448 kg), and dried under vacuum at 50° C. to afford the titlecompound (45.5 kg).

Alternative Preparation of cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide, (L) malate salt

Cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (47.9 kg), L-malic acid (17.2 kg), methyl ethylketone (658.2 kg), and water (129.1 kg) were charged to a reactor, andthe mixture was heated 50-55° C. for approximately 1-3 hours, and thenat 55-60° C. for an additional 4-5 hours. The mixture was clarified byfiltration through a 1 μm cartridge. The reactor temperature wasadjusted to 20-25° C. and vacuum distilled with a vacuum at 150-200 mmHg with a maximum jacket temperature of 55° C. to the volume range of558-731 L.

The vacuum distillation was performed two more times with the charge of380 kg and 380.2 kg methyl ethyl ketone, respectively. After the thirddistillation, the volume of the batch was adjusted to 18 v/w ofcyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide by charging methyl ethyl ketone (159.9 kg) togive a total volume of 880 L. An additional vacuum distillation wascarried out by adjusting methyl ethyl ketone (245.7 kg). The reactionmixture was left with moderate agitation at 20-25° C. for at least 24hours. The product was filtered and washed with methyl ethyl ketone415.1 kg) in three portions. The product was dried under a vacuum withthe jacket temperature set point at 45° C.

In an alternative procedure, the order of addition was changes so that asolution of L-malic acid (17.7 kg) dissolved in water (129.9 kg) wasadded to Cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (48.7 kg) in methyl ethyl ketone (673.3 kg).

General Methods of Analysis of Crystalline Forms of Compound I andCompound I, Malate Salt

Crystalline forms may be prepared by a variety of methods including, butnot limited to, crystallization or recrystallization from a suitablesolvent mixture, sublimation, growth from a melt, solid statetransformation from another phase, crystallization from a supercriticalfluid, and jet spraying. Techniques for crystallization orrecrystallization of crystalline forms of a solvent mixture include, butare not limited to, evaporation of the solvent, decreasing thetemperature of the solvent mixture, crystal seeding of a supersaturatedsolvent mixture of the compound and/or salt thereof, crystal seeding asupersaturated solvent mixture of the compound and/or a salt fromthereof, freeze drying the solvent mixture, and adding antisolvents(countersolvents) to the solvent mixture. High throughputcrystallization techniques may be employed to prepare crystalline formsincluding polymorphs.

Crystals of drugs, including polymorphs, their methods of preparation,and the characterization of drug crystals, are discussed in Solid-StateChemistry of Drugs, S. R. Byrn, R. R. Pfeiffer, and J. G. Stowell,2^(nd) Edition, SSCI, West Lafayette, Ind. (1999).

In a crystallization technique in which a solvent is employed, thesolvent is typically chosen based on one or more factors including, butnot limited to, solubility of the compound, crystallization techniqueutilized, and vapor pressure of the solvent. Combinations of solventsmay be employed. For example, the compound may be solubilized in a firstsolvent to afford a solution, followed by the addition of an antisolventto decrease the solubility of the compound in the solution andprecipitate the formation of crystals. An antisolvent is a solvent inwhich a compound has low solubility.

In one method that can be used in preparing crystals, the L-malate saltof Compound I can be suspended and/or stirred in a suitable solvent toafford a slurry, which may be heated to promote dissolution. The term“slurry,” as used herein, means a saturated solution of the compound,wherein such solution may contain an additional amount of compound toafford a heterogeneous mixture of compound and solvent at a giventemperature.

Seed crystals may be added to any crystallization mixture to promotecrystallization. Seeding may be employed to control growth of aparticular polymorph and/or to control the particle size distribution ofthe crystalline product. Accordingly, calculation of the amount of seedsneeded depends on the size of the seed available and the desired size ofan average product particle as described, for example, in ProgrammedCooling Batch Crystallizers,” J. W. Mullin and J. Nyvlt, ChemicalEngineering Science, 1971, 26, 3690377. In general, seeds of small sizeare needed to effectively control the growth of crystals in the batch.Seeds of small size may be generated by sieving, milling, or micronizinglarge crystals, or by microcrystallizing a solution. In the milling ormicronizing of crystals, care should be taken to avoid changingcrystallinity from the desired crystalline form (i.e., changing to anamorphous or other polymorphic form).

A cooled crystallization mixture may be filtered under vacuum and theisolated solid product washed with a suitable solvent, such as, forexample, cold recrystallization solvent. After washing, the product maybe dried under a nitrogen purge to afford the desired crystalline form.The product may be analyzed by a suitable spectroscopic or analyticaltechnique including, but not limited to, differential scanningcalorimetry (DSC), x-ray powder diffraction (XRPD), andthermogravimetric analysis (TGA), to ensure that the crystalline form ofthe compound has been formed. The resulting crystalline form may beproduced in an amount greater than about 70 weight percent isolatedyield, based on the weight of the compound originally employed in thecrystallization procedure, and preferably greater than about 90 weightpercent isolated yield. Optionally, the product may be delumped bycomilling or passing through a mesh screen.

Preparation of Crystalline L-Malate Salt of Compound I

The preparation of the captioned salt and its characterization isdescribed above and in WO 2010/083414, the entire contents of which isincorporated by reference.

Solid State Nuclear Magnetic Resonance (SSNMR)

All solid-state ¹³C NMR measurements were made with a Bruker DSX-400,400 MHz NMR spectrometer. High resolution spectra were obtained usinghigh-power proton decoupling, the TPPM pulse sequence, and rampamplitude cross-polarization (RAMP-CP) with magic-angle spinning (MAS)at approximately 12 kHz (A. E. Bennett et al, J. Chem. Phys., 1995, 103,6951 and G. Metz, X. Wu and S. O. Smith, J. Magn. Reson. A., 1994, 110,219-227). Approximately 70 mg of sample, packed into a canister-designzirconia rotor, was used for each experiment. Chemical shifts (δ) werereferenced to external adamantane with the high frequency resonancebeing set to 38.56 ppm (W. L. Earl and D. L. VanderHart, J. Magn.Reson., 1982, 48, 35-54).

L-Malate Salt of Compound I

The solid state ¹³C NMR spectrum of the crystalline L-malate salt ofCompound I provides the following list of peaks, or a subset thereof,may be sufficient to characterize crystalline L-malate salt of CompoundI.

SS ¹³C NMR Peaks: 18.1, 20.6, 26.0, 42.9, 44.5, 54.4, 55.4, 56.1, 70.4,99.4, 100.1, 100.6, 114.4, 114.9, 115.8, 119.6, 120.1, 121.6, 123.2,124.1, 136.4, 138.6, 140.6, 145.4, 150.1, 150.9, 156.2, 157.4, 159.4,164.9, 167.1, 170.8, 175.7, and 182.1 ppm, ±0.2 ppm.

The solid state ¹⁵N NMR spectrum of the crystalline L-malate salt ofCompound I. provides peaks at 118.6, 119.6, 120.7, 134.8, 167.1, 176.0,and 180 ppm, ±0.2 ppm. The entire list of peaks, or a subset thereof,may be sufficient to characterize crystalline L-malate salt of CompoundI.

The solid state ¹⁹F NMR spectrum of the crystalline L-malate salt ofCompound I. provides peaks at −121.6, −120.8, and −118.0 ppm, ±0.2 ppm.

Thermal Characterization Measurements

Thermal Gravimetric Analysis (TGA)

TGA measurements were performed in a TA Instruments™ model Q500 or 2950,employing an open pan setup. The sample (about 10-30 mg) was placed in apreviously tared platinum pan. The weight of the sample was measuredaccurately and recorded to a thousand of a milligram. The furnace waspurged with nitrogen gas at 100 mL/min. Data were collected between roomtemperature and 300° C. at 10° C./min heating rate.

Differential Scanning calorimetry (DSC) Analysis

DSC measurements were performed in a TA Instruments™ models Q2000, 1000,or 2920, employing an open pan setup. The sample (about 2-6 mg) wasweighed in an aluminum pan, accurately recorded to a hundredth of amilligram, and transferred to the DSC. The instrument was purged withnitrogen gas at 50 mL/min. Data were collected between room temperatureand 300° C. at a 10° C./min heating rate. The plot was made with theendothermic peaks pointing down.

L-Malate Salt of Compound I

The TGA thermogram for the crystalline L-malate salt of Compound I,which shows a weight loss of approximately 0.4 weight percent at atemperature of 170° C.

The DSC thermogram for the crystalline L-malate salt of Compound I,which showed a melting point of approximately 187° C.

Moisture Vapor Isotherm Measurements

Moisture sorption isotherms were collected in a VTI SGA-100 SymmetricVapor Analyzer using approximately 10 mg of sample. The sample was driedat 60° C. until the loss rate of less than or equal to 0.0005 weightpercent per minute was obtained for 10 minutes. The sample was tested at25° C. and a relative humidity (RH) of 3, 4, 5, 15, 25, 35, 45, 50, 65,75, 85, and 95 percent. Equilibration at each RH was reached when therate of less than or equal to 0.0003 weight percent per minute for 35minutes was achieved, or at a maximum of 600 minutes.

All ranges disclosed herein are inclusive of the endpoints, and theendpoints are independently combinable with each other.

The use of the terms “a”, “an”, “the”, and similar referents in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. Further, it should be noted that the terms “first,” “second,”and the like herein do not denote any order, quantity, or importance,but rather are used to distinguish one element from another. Themodifier “about” used in connection with a quantity is inclusive of thestated value and has the meaning dictated by the context (e.g., itincludes the degree of error associated with measurement of theparticular quantity).

The foregoing disclosure has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications can be made while remainingwithin the spirit and scope of the invention. It will be obvious to oneof skill in the art that changes and modifications can be practicedwithin the scope of the appended claims. Therefore, it is to beunderstood that the above description is intended to be illustrative andnot restrictive. The scope of the invention should, therefore, bedetermined not with reference to the above description, but shouldinstead be determined with reference to the following appended claims,along with the full scope of equivalents to which such claims areentitled.

What is claimed is:
 1. A tablet pharmaceutical composition comprisingabout: Ingredient (% w/w) Compound I, L-malate salt 31.68Microcrystalline Cellulose 38.85 Lactose anhydrous 19.42 HydroxypropylCellulose 3.00 Croscarmellose Sodium 3.00 Total Intra-granular 95.95Silicon dioxide, Colloidal 0.30 Croscarmellose Sodium 3.00 MagnesiumStearate 0.75 Total 100.00

wherein Compound I is:

Compound I.
 2. A tablet pharmaceutical composition comprising: 30-32percent by weight of Compound I, L-malate salt wherein Compound I is:

38-40 percent by weight of microcrystalline cellulose; 18-22 percent byweight of lactose; 2-4 percent by weight of hydroxypropyl cellulose; 4-8percent by weight of croscarmellose sodium; 0.2-0.6 percent by weight ofcolloidal silicon dioxide; and 0.5-1 percent by weight of magnesiumstearate.
 3. The tablet pharmaceutical composition of claim 2, furthercomprising a film coating containing hypromellose, titanium dioxide,triacetin, and iron oxide yellow.
 4. The tablet pharmaceuticalcomposition of claim 1, further comprising a film coating containinghypromellose, titanium dioxide, triacetin, and iron oxide yellow.
 5. Thetable pharmaceutical composition of claim 1, containing 20 to 100 mg ofCompound I.
 6. The tablet pharmaceutical composition of claim 1,containing 20, 25, 50, 60, 75, 80, or 100 mg of Compound I.
 7. A tabletpharmaceutical composition comprising, based on 100 weight/weightpercent: 30-32 percent by weight of Compound I, L-malate salt whereinCompound I is:

38-40 percent by weight of microcrystalline cellulose; 18-22 percent byweight of lactose 2-4 percent by weight of hydroxypropyl cellulose; 4-8percent by weight of croscarmellose sodium; 0.2-0.6 percent by weight ofcolloidal silicon dioxide; and 0.5-1 percent by weight of magnesiumstearate; and further comprising a film coating containing hypromellose,titanium dioxide, triacetin, and iron oxide yellow.
 8. The tabletpharmaceutical composition of claim 7, containing 20 to 100 mg ofCompound I.
 9. The tablet pharmaceutical composition of claim 7,containing 20, 25, 50, 60, 75, 80, or 100 mg of Compound I.
 10. A tabletpharmaceutical composition comprising: Ingredient (% w/w) Compound I,L-malate 31.68 salt Microcrystalline Cellulose 38.85 Lactose anhydrous19.42 Hydroxypropyl Cellulose 3.00 Croscarmellose Sodium 6.00 Silicondioxide, Colloidal 0.30 Magnesium Stearate 0.75 Total 100.00.

wherein Compound I is:


11. The tablet pharmaceutical composition of claim 2, containing 20 to100 mg of Compound I.
 12. The tablet pharmaceutical composition of claim2, containing 20, 25, 50, 60, 75, 80, or 100 mg of Compound I.